1. Field of the Invention
The present invention relates generally to the fields of endocrinology and neuroendocrinology. More specifically, the present invention relates to the corticotropin releasing factor receptor-1 and animals deficient in the corticotropin releasing factor receptor-1 receptor.
2. Description of the Related Art
Survival of an organism is dependent on maintenance of homeostasis in response to stressful conditions. Homeostasis is maintained through adaptational responses geared to counteract the effects of aversive stimuli (Chrousos et al., 1992). Generally, these adaptive responses result from the stimulation of neural pathways linked to self protection, such as attention, arousal and aggression, and the inhibition of pathways that promote vegetative functions such as growth, reproduction and feeding (Chrousos et al., 1992). In mammals, corticotropin releasing factor (CRF) is a major integrator of the endocrine, neuroendocrine, autonomic and behavioral responses to stress (Owens & Nemeroff, 1991; Vale et al., 1981). Dysregulation of the stress response results in quite severe psychological and physiological consequences. Indeed, chronic hyperactivation of the corticotropin releasing factor system has been linked to many affective disorders, such as anxiety, anorexia nervosa and melancholic depression (Chrousos et al., 1992; Orth, 1992).
In addition to its role in the stress response, corticotropin releasing factor is also implicated in the control of cognitive function. Corticotropin releasing factor is known to increase learning and memory in rodents (Behan et al., 1995, Diamant & de Wied, 1993, Koob & Bloom, 1985, Liang & Lee, 1988) and alterations in the corticotropin releasing factor system are associated with several neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (De Souza, 1995). However, the developmental and physiological actions of corticotropin releasing factor dependent pathways involved in these stress related phenomena and in cognitive function are not completely understood.
The pleiotropic nature of the corticotropin releasing factor system was recently expanded with the discovery of urocortin (UCN), a second mammalian member of the corticotropin releasing factor family. Urocortin, characterized from rat midbrain, shares only 45% sequence similarity with corticotropin releasing factor (Vaughan et al., 1995). While the exact function of urocortin is not known, this peptide can mimic many of the biological actions of corticotropin releasing factor in vitro and in vivo (Spina et al., 1996; Turnbull et al., 1996; Vaughan et al., 1995), although with a different potency profile.
The biological actions of corticotropin releasing factor family members are mediated via binding to specific high affinity membrane receptors belonging to the subfamily of G-protein coupled receptors for small ligands including secretin, vasoactive intestinal polypeptide and growth hormone releasing factor (Segre & Goldring, 1993). Two distinct corticotropin releasing factor receptor subtypes, corticotropin releasing factor receptor-1 and corticotropin releasing factor receptor-2, have been characterized from several species (Grigoriadis et al., 1996; Vale et al., 1997). Corticotropin releasing factor receptor-1 and corticotropin releasing factor receptor-2 share approximately 71% amino acid sequence similarity (Grigoriadis et al., 1996; Vale et al., 1997) and are both pharmacologically distinct and unique in their expression patterns within the brain and in peripheral tissues. In the adult, expression of corticotropin releasing factor receptor-1 is limited primarily to regions of the brain including the brain stem, cerebellum, cerebral cortex, and medial septum and also to the pituitary gland (Chalmers et al., 1995; Potter et al., 1994).
In contrast, corticotropin releasing factor receptor-2 is expressed in several peripheral tissues including the heart, skeletal muscle, gastrointestinal tract and the epididymis (Kishimoto et al., 1995; Lovenberg et al., 1995; Perrin et al., 1995; Stenzel et al., 1995), and expression within the brain is most prevalent in the lateral septum and hypothalamic areas (Chalmers et al., 1995; Perrin et al., 1995). While each receptor subtype can bind both corticotropin releasing factor and urocortin, urocortin displays an approximately 40 fold higher affinity for corticotropin releasing factor receptor-2 than does corticotropin releasing factor (Vaughan et al., 1995). These results suggest that urocortin may be the putative endogenous ligand for corticotropin releasing factor receptor-2. However, the specific corticotropin releasing factor receptor molecules that trigger each of the various adaptive responses to averse stimuli have not been clearly established.
The developmental role of the various components of the corticotropin releasing factor system has not been fully elucidated. Expression of corticotropin releasing factor is temporally and spatially regulated during embryonic and neonatal development and mice null for the corticotropin releasing factor gene display endocrine and developmental abnormalities (Muglia et al., 1995). In addition, corticotropin releasing factor receptors are present within distinct regions of the rat brain as early as embryonic day 15 and expression is developmentally regulated during early neonatal life (Avishai-Eliner et al., 1996; Insel et al., 1988). However, the presence of multiple corticotropin releasing factor receptor subtypes and additional corticotropin releasing factor related ligands necessitates a systematic evaluation of the biological pathways mediated by each corticotropin releasing factor receptor subtype.
Thus, the prior art is deficient in understanding the role of the corticotropin releasing factor system, the corticotropin releasing factor receptor subtypes in development and animals deficient in the corticotropin releasing factor receptor-1 receptor. The present invention fulfills this longstanding need and desire in the art.